Poly(adenosinediphosphate-ribose)-polymerase (poly(ADP-ribose)-polymerase, PARP) is a new target for cancer therapy, which catalyzes and transfers ADP-ribose units from nicotinamide adenine Dinucleotide (NAD+) to various receptor proteins. PARP is involved in DNA repair and transcriptional regulation. It not only plays a key role in regulating cell survival and death, but also is the main transcription factor in tumor development and inflammation.
PARP-1 is the first discovered member of the PARP family and has been extensively researched. It is a ribozyme consisting of 1014 amino acid residues, has a relative molecular mass of 116 ku, and plays a leading role in single-strand DNA repair. As a DNA gap receptor, PARP-1 is activated after DNA damage, recognizes and binds to DNA damage site, reduces DNA recombination, and prevents damaged DNA from being affected by exonuclease. After binding to the DNA damage site, the catalytic activity of PARP-1 is increased 10-fold to 500-fold, and NAD+ is catalytically decomposed into nicotinamide and ADP ribose by autoglycosylation and formation of a homodimer. Using ADP ribose as a substrate, the nuclear receptor protein (mainly PARP itself) forms a linear or linear PARP-1-ADP ribose polymer. These poly ADP ribose polymers with more negative charge and higher steric hindrance can not only prevent the nearby DNA molecules from recombining with the damaged DNA, but also reduce the affinity of PARP-1 to DNA, dissociating PARP-1 from the DNA damage site and guiding DNA repair enzyme to bind to the DNA damage site to repair the damage site. The dissociated PARP-1-ADP ribose polymer is cleaved by poly(ADP-ribose) glycohydrolase (PARG), and the lysed ADP ribose is re-used for synthesizing NAD+. After PARP-1 was dissociated from the ADP ribose polymer, it is reactivated and bound to DNA, and the DNA damage repair process is repeated. However, the over-expression of DNA repair enzymes in tumor cells activates its own DNA damage repair mechanism, which in turn produces resistance during drug therapy and radiation therapy. Studies have found that PARP inhibitors can block the DNA repair pathway and reduce the self-repairing ability of tumor cells. Therefore, the combination of PARP inhibitors and chemoradiotherapy can effectively enhance the anti-tumor effect. The studies also found that PARP inhibitors alone have a significant inhibitory effect on breast cancer and ovarian cancer with BRCA1/2 gene deletion or mutation.
In summary, PARP inhibitor has broad application in antitumor research and therapy. Chinese Patent Application No. 2015102677321 discloses azaphenalene-3-one derivative, a process for preparing the same and its application as a PARP inhibitor. The azaphenalene-3-one derivative has the following structure:
In the structure, R is hydrogen, methyl, ethyl, isopropyl, benzyl or 3-methyl-3-butenyl. The azaphenalene-3-one derivative has a high activity of inhibiting PARP enzyme, and can be used as a good foundation for the development of azaphenalene-3-one derivative as PARP inhibitors to treat tumor, but its synthesis is difficult. The yield and product purity are low, and post-treatment is difficult. In the synthetic route, toxic reagents, such as acetic anhydride, phosphorus oxychloride and sulfuric acid, were used. The number of compounds prepared was small, and the success rate was low, which is not suitable for screening of a large number of compounds. Therefore, based on the previous research, the present invention intends to design and synthesize a series of new azaphenalene-3-one derivatives based on pyridazinone nucleus. Preliminary study of their activity was also conducted, which establishes a good foundation for researching better anti-tumor drugs.